Potential MASH Target Identified as Gene Deletion Triggers Liver Symptoms in Mice

Researchers at Waseda University in Japan have made a significant breakthrough in the understanding of metabolic dysfunction-associated steatohepatitis (MASH), identifying a potential new target for therapeutic intervention. The study, published in Communications Biology on March 11, 2025, reveals that disrupting the Nwd1 gene in mice leads to liver symptoms characteristic of MASH, suggesting that the protein produced by this gene could be a promising focus for future treatments.

Gene Disruption Mimics MASH Symptoms

Using CRISPR gene editing technology, the research team rendered the Nwd1 gene nonfunctional in mice. The resulting effects closely mirrored the symptoms of MASH in humans, with the rodents' liver cells becoming enlarged with fat molecules and their livers developing scar tissue. These observations are consistent with the pathology of MASH, where patients' livers accumulate fat deposits that can progress to scarring, cirrhosis, and potentially liver failure.

The study's findings indicate that the Nwd1 protein, formally known as NACHT and WD repeat domain-containing protein 1, plays a crucial role in liver function. Previously, the protein was known to be important for brain development, but its hepatic function remained unclear until now.

Molecular Mechanisms and Potential Therapeutic Implications

Further investigation revealed that the loss of Nwd1's regulatory function decreased the activity of SERCA2 ATPase, a protein that has been previously identified as a potential target for MASH therapeutics. This reduction in SERCA2 ATPase activity led to lower calcium levels inside the cells' endoplasmic reticula (ER), an organelle critical for protein folding and lipid transfer.

The researchers noted that disruption of ER activity has been linked to MASH, suggesting that the Nwd1-SERCA2 ATPase pathway could be a key mechanism in the disease's pathogenesis. The study's authors proposed that "unraveling the function of Nwd1 could provide clues to understanding the mechanisms of MASH pathogenesis and developing therapeutic strategies for MASH associated with ER stress."

MASH: A Growing Market with Recent Breakthroughs

This discovery comes at a time when MASH is increasingly recognized as a significant health concern. A study published in January 2025 projected that MASH cases in the United States would rise from 14.9 million adults in 2020 to 23.2 million by 2050, underscoring the urgent need for effective treatments.

The pharmaceutical industry has long struggled to develop successful MASH therapies, with numerous companies facing setbacks in clinical trials. However, a major milestone was achieved in March 2024 with the FDA approval of Madrigal Pharmaceuticals' Rezdiffra (resmetirom), the first drug specifically approved for MASH. Since its launch, Rezdiffra has demonstrated commercial success, generating $180 million in sales during its first nine months on the market.

The identification of Nwd1 as a potential therapeutic target adds to the growing arsenal of approaches being explored to combat MASH. As research continues to unravel the complex mechanisms underlying this disease, the pharmaceutical industry remains poised to address the increasing demand for effective MASH treatments in the coming years.